Psoralen is a linear three ring heterocyclic compound of the general structure ##STR1## It is a bifunctional photoreactive molecule which forms covalent bonds with nucleic acids in the presence of near ultraviolet light. Psoralen's ability to react with DNA has given it clinical importance in the treatment of various skin disorders, and its ability to form interstrand crosslinks in double stranded DNA has made it a useful agent in the study of nucleic acid structure and function.
For over 10 years, patients with psoriasis have been treated with orally administered psoralens and subsequently irradiated with long wave ultraviolet-A radiation (PUVA). Currently, the only psoralen commercially available for oral administration is 8-methoxypsoralen (8-MOP). Since psoralens are lipophilic compounds, poorly soluble in water, one current oral preparation consists of 8-MOP mixed with polyethylene glycols in a soft gelatin capsule. The oral absorption of 8-MOP from this dosage form varies considerably between individuals, so peak serum psoralen levels may occur as early as 1 hour or as late as 4 hours after the capsule is administered. The subject is treated with ultraviolet A irradiation approximately two hours after oral administration of the dosage form. Because the oral absorption of 8-MOP from the capsule is variable, serum levels of 8-MOP at 2 hours post dosing may not be optimal. Since serum levels of 8-MOP and photosensitivity are directly correlated, less than optimal 8-MOP serum levels may be one factor in a poor response to PUVA therapy.
Other routes of administration for 8-MOP have been used. In the United States 8-MOP is available as a topical lotion. In Europe 8-MOP has been applied topically using baths. PUVA baths are effective but inconvenient, and topical absorption of 8-MOP is variable resulting in a lack of predictability of the phototoxic response. PUVA baths have thus not gained wide appeal.
Serum levels and photosensitivity are more predictable with rectally administered 8-MOP resulting in good therapeutic response. However, the inconvenience of rectal administration is likely to deter widespread popularity.
Other oral dosage forms comprise solutions of psoralens dissolved in alcohols and/or polyethylene glycols or are oil-on-water emulsions; or are semi-solid capsule dosage forms wherein the average crystal size of the psoralen is greatly reduced. These dosage forms have improved the consistency of PUVA therapy but the unpredictability of oral administration of psoralens still results in inconsistent responses to photophoresis therapy.
Accordingly, there is still a need for a psoralen dosage form which provides consistent results when psoralens are used in conjunction with ultraviolet-A phototherapy to alleviate disease.